TY  - CHAP
M1  - Book, Section
TI  - Pharmacology and Toxicity of Antineoplastic Drugs
A1  - Izar, Benjamin
A1  - Dzube, Dustin
A1  - Cleary, James M.
A1  - Mitsiades, Constantine S.
A1  - Richardson, Paul G.
A1  - Barnes, Jeffrey A.
A1  - Chabner, Bruce A.
A2  - Kaushansky, Kenneth
A2  - Lichtman, Marshall A.
A2  - Prchal, Josef T.
A2  - Levi, Marcel M.
A2  - Press, Oliver W.
A2  - Burns, Linda J.
A2  - Caligiuri, Michael
PY  - 2015
T2  - Williams Hematology, 9e
AB  - SUMMARYThe  safe  and  effective  use  of  anticancer  drugs  in  the  treatment  of  hematologic  malignancies  requires  an  in-depth  knowledge  of  the  pharmacology  of  these  agents.  In  this  field  of  medicine,  the  margin  of  safety  is  narrow  and  the  potential  for  serious  toxicity  is  real.  At  the  same  time,  anticancer  drugs  cure  many  hematologic  malignancies  and  provide  palliation  for  others.  The  discovery  and  development  of  treatments  for  leukemia  and  lymphoma  have  provided  a  paradigm  for  approaches  to  the  improved  treatment  of  the  more  common  solid  tumors.The  intelligent  use  of  these  drugs  begins  with  an  understanding  of  their  mechanism  of  action.  Cytotoxic  anticancer  drugs  inhibit  the  synthesis  of  DNA  or  directly  attack  its  integrity  through  the  formation  of  DNA  adducts  or  enzyme-mediated  breaks.  These  DNA-directed  actions  are  recognized  by  repair  processes  and  by  the  checkpoints  that  monitor  DNA  integrity,  including  most  prominently  p53.  If  DNA  damage  cannot  be  repaired,  and  if  the  DNA  damage  reaches  thresholds  for  activating  programmed  cell  death,  then  DNA  damage  is  translated  into  tumor  regression.  Attention  has  turned  to  the  possibility  of  identifying  molecular  targets  unique  to  tumor  cells,  or  dramatically  overexpressed  in  those  cells,  including  molecules  involved  in  cell  signaling  and  cell-cycle  control,  but  the  principles  of  drug  action  and  resistance  to  these  compounds  remain  the  same.  Resistance  to  drug  action  can  arise  from  alterations  in  any  one  of  the  critical  steps  required  for  drug  activity;  these  steps  include  drug  uptake  and  distribution  through  the  bloodstream  or  across  the  blood–brain  barrier;  transport  across  the  cell  membrane;  transformation  of  the  parent  drug  to  its  active  form  within  the  tumor  cell  or  in  the  liver;  interaction  of  the  drug  with  its  target  protein  or  nucleic  acid;  enzymatic  or  chemical  inactivation  of  the  agent;  drug  transport  out  of  the  cell;  and  elimination  of  the  agent  from  the  body  through  the  kidneys  or  through  metabolic  transformation.  The  underlying  mutability  of  tumors  leads  to  the  spontaneous  generation  of  cells  with  alterations  in  drug  uptake,  transformation,  inactivation,  and  target  binding.  In  the  presence  of  the  selective  pressure  of  drug,  resistant  tumors  replace  sensitive  cells  as  the  dominant  tumor  population.  Combination  chemotherapy  overcomes  resistance  that  carries  specificity  for  single  agents,  but  the  expression  of  multidrug  resistance  genes,  as  well  as  loss  of  the  apoptotic  response,  can  result  in  resistance  even  to  combination  drug  therapy.In  addition  to  the  molecular  determinants  of  drug  action,  pharmacokinetics  (the  disposition  of  drugs  in  humans)  plays  a  critical  role  in  determining  drug  effectiveness  and  toxicity.  Drug  regimens  are  designed  to  achieve  a  maximally  effective  concentration  in  plasma  and  tumor  cells  for  an  effective  duration  of  exposure.  Because  of  the  potential  of  these  agents  for  toxicity,  it  is  critical  for  hematologists  and  oncologists  to  understand  the  pathways  of  drug  clearance  and  to  adjust  dose  in  the  presence  of  compromised  organ  function.  Drugs  such  as  methotrexate,  hydroxyurea,  and  the  newer  purine  antagonists  (fludarabine  and  cladribine)  are  eliminated  primarily  by  renal  excretion  and  should  not  be  used  in  full  doses  in  patients  with  renal  dysfunction.  Similarly,  hepatic  dysfunction  with  an  elevated  serum  bilirubin  concentration  should  alert  ...
SN  - 
PB  - McGraw-Hill Education
CY  - New York, NY
Y2  - 2024/04/20
UR  - hemonc.mhmedical.com/content.aspx?aid=1121090411
ER  -